生物活性

MK-1775 is a potent and selective Wee1 inhibitor (IC50= 5.2 nM); hinders G2 DNA damage checkpoint.

MK-1775inhibited phosphorylation of CDC2 without chemotherapy was 49 nM in WiDr cells.

Kinaseactivity{1][2]

Cell viability

体外研究

体内研究

0.5% methylcellulose

激酶实验

Invitro Kinase Assays[1]

Recombinant human Wee1 was purchased. Kinasereaction was conducted with 10μmol/ L

ATP, 1.0μCi of [γ-33P]ATP, and2.5μg of poly(Lys, Tyr) as a substrate at 30°C for 30 min. Ra dioactivityincorporated into the substrate was trapped on MultiScreen-PH plates and was countedon a liquid scintillation counter.

细胞实验

Cellculture[3]

The THP-1, MV4-11, U937,HL-60, OCI-AML3, MOLM-13, CTS cell lines were cultured in RPMI 1640 (exceptOCI-AML3, which was cultured in alpha-MEM) with 10-15% fetal bovine serum, 2mML-glutamine, 100 U/ml penicillin and 100μg/ml streptomycin. All cells werecultured in a 37°C humidified atmosphere containing 5% CO2/95% air.

Invitro cytotoxicity assays

In vitro cytotoxicity of the AML cells weremeasured by using MTT (3-[4, 5-dimethyl-thiazol-2-yl]-2,5-diphenyltetrazoliumbromide)assays. Briefly, the cells were treated with variable concentrations of MK-1775for 72 hours. MTT was added to a final concentration of 1mM and cells wereincubated for 4 hours at 37°C. The cells were lysed overnight using 10% SDS in10mM HCL and plates were read at 590 nm using a microplate reader. IC50 valueswere calculated as drug concentrations necessary to inhibit 50% growth comparedto vehicle control treated cells.

动物实验

Invivo studies[2]

CD-1 nu/nu female mice aged 5 to 6 weekswere fed 2018S autoclaveable diet and water ad libitum. Mice were inoculated with5 x 106cells (1:1 Matrigel:PBS) for A427 and LoVo models or with 1mm3tumor fragments for the SK-MES-1 model, subcutaneously into theright flank. When tumor volume reached 200 mm3(±50), mice were pair-matched so each group had a similar mean and SD.Mice received anywhere from 13 to 28 days of either vehicle (0.5%methylcellulose) or MK-1775 at 60 mg/kg, both administered twice daily at adosing volume of 10 mL/kg (0.2 mL per 20 g mouse). Tumor volume and bodyweights were recorded biweekly. Percent TGI was calculated as 100 - (100 xΔT/ΔC) ifΔT > 0 whereΔT = finalmean volume initial mean volume of treated group andΔC = final mean volume - initial mean volume of vehicle control group

.

不同实验动物依据体表面积的等效剂量转换表（数据来源于FDA指南）

例如，已知某工具药用于小鼠的剂量为88 mg/kg , 则用于大鼠的剂量换算方法：将88 mg/kg 乘以小鼠的Km系数（3），再除以大鼠的Km系数（6），得到该药物用于大鼠的等效剂量44 mg/kg。

参考文献

[1] Hirai H, Iwasawa Y, Okada M, et al. Small-molecule inhibition of Wee1 kinase by MK-1775 selectively sensitizes p53-deficient tumor cells to DNA-damaging agents. Mol Cancer Ther. 2009;8(11):2992-3000.
[more]

体内溶解度
约28 mg/mL

Clinical Trial Information ( data from http://clinicaltrials.gov )

注：以上所有数据均来自公开文献，并不保证对所有实验均有效，数据仅供参考。

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